CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. Calcitonin gene-related peptide (CGRP) is a potent vasodilatory neurotransmitter believed to play a key role in migraine pathophysiology. The initial human clinical validation of the CGRP target was provided by Boehringer Ingelheim in 2003 with the report that an IV formulation comprising olcegepant was efficacious in the acute treatment of migraine and the mechanism was confirmed by a study using telcagepant (a CGRP antagonist) in an oral formulation.
Newly developed CGRP antagonist compounds are described in published international application, publication no. WO 2012/064910, which are based on the structure of Formula I:
where “Ra” is various substituents (for example, where “Ra” is hydrogen: (S)—N-((3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide and, for example, where three of “Ra” are selected to be fluorine: (S)—N-((3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)-2′-oxo-1′,2′,5,7-tetrahydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridine]-3-carboxamide). These compounds show promise as well-tolerated, potent CGRP-antagonist with low potential for side effects and metabolic complications. However, these compounds have low solubility and in general do not form salts suitable for the preparation of a stable pharmaceutical formulation.
For initial in vivo study it is common to administer poorly-soluble “class II” compounds formulated as a liquid formulation, for example, as a cosolvent or lipid-based solution employing a cosolvent such as PEG400, and other constituents as needed, to facilitate dissolution and enhance oral absorption. Although useful for clinical studies, in general it is not commercially attractive to provide a liquid formulation for oral delivery of medications for use in therapy for acute or chronic conditions or for use in prophylaxis treatment of chronic conditions. Desirably, such medicaments should be in a solid form for oral administration, for example, a pressed tablet or a capsule containing the API. In general, however, drugs with poor aqueous solubility are difficult to deliver in the gastrointestinal system without some solubility enhancer or permeation enhancer, or both, present at the site of absorption.
Solid dispersions, and, particularly, solid solutions, have been employed to promote the oral absorption of poorly water soluble active pharmaceutical ingredients (APIs), see, for example, Ford, Pharm Acta Helv, 1986, 61:69-88. Solid dispersions and solid solutions are compositions in which API is dispersed into or dissolved in a solid matrix, generally a polymer matrix. Solid solutions and solid dispersions (in which the active pharmaceutical ingredient forms a homogeneous or nearly homogeneous glass in the excipient matrix) are of particular interest in the oral delivery of poorly water soluble compounds. It is believed that these materials improve the absorption of orally administered API by improving: (i) the wetting properties of the API; (ii) causing at the point of absorption transient supersaturation of the API with respect to a lower energy (e.g. crystalline) phase API; or (iii) both effects. In general, solid solutions are believed to enable drug absorption by enhancing the dissolution rate and/or the extent to which the drug is dissolved from the matrix.
One example of a Class II drug which has been formulated as a solid solution is posaconazole, as described in International Patent Application, publication no. WO2009/129300, published Oct. 22, 2009. Such compositions of posaconazole were prepared by forming an extrudate of posaconazole in hydroxypropylmethylcellulose acetate-succinate-derivatized polymer (HPMC-AS), which solid dispersion was subsequently blended with microcrystalline cellulose, additional HPMC-AS, hydroxypropylcellulose, and magnesium sterate. This admixture was tableted to provide an orally bioavailable posaconazole formulation with desirable PK and bioavailability.
Another example of polymers employed in providing a solid solution of polymer and API is reported by Goertz et al. in U.S. Pat. No. 4,801,460 describes solid dispersions comprising a poorly soluble drug (exemplified by theophylline) and cross-linked polyvinylpyrrolidone/vinyl acetate copolymer (PVP copolymer). The '460 patent reports drug release times of up to 8 hours in tests, and does not discuss instant release medicaments employing such polymer matrix solid solutions.
In another example, in published international application publication no. WO98/029137 (the '137 publication), published Jul. 9, 1998, Takagi et al. describes compositions comprising an API dissolved in a matrix comprising a cellulosic polymer, for example, hydroxypropylmethyl-, hydroxyethyl- and hydroxypropyl-cellulose, and salts having an endothermic heat of dissolution, for example, sodium bicarbonate, which is said to improve the rate of disintegration. The '137 publication identifies the compositions taught therein as being similar to admixtures employing a carbonate or bicarbonate salt in the presence of a solid, water soluble acid which aids disintegration when exposed to an aqueous environment via effervescent action.
In another example, Fry et al. describe formulations of HER-2 inhibitors dispersed in a wide variety of polymer matricies, including many different derivatives of cellulosic polymers (including graft copolymers incorporating cellulosic moieties), polyvinyl alcohol polymers and polyvinylpyrrolidine polymers. See published international application publication no. WO2013/056108, published Apr. 18, 2013. Such compositions are said to reduce interpatient PK variability.
Despite their growing use, the design of solid solution formulations to effectively promote oral drug absorption remains largely a matter of trial and error. Successful formulation of lipophilic compounds as solid dispersions to promote oral absorption may benefit from a strong interaction between API and polymer. This has led to interest in partially water soluble polymers with amphiphilic properties like hydroxypropyl methylcellulose acetate succinate (HPMCAS), especially when the process used to create the solid dispersion is spray drying. See Friesen et al., Mol. Pharm., 2008, 5:1003-1019. While this approach was successful for many drug candidates, it was suggested that compounds with high melting points (or high ratios of melting point to glass transition temperature) and/or particularly lipophilic compounds (e.g., those with high log P values) are especially problematic to successfully formulate as solid solutions. Friesen et al. suggests that successful formulations of compounds having high melting point properties will likely be limited to relatively dilute concentrations of API in the solid dispersion.
As will be appreciated from the foregoing, while it is desirable to provide compounds of Formula I in the form of a solid for oral dosing administered via the GI tract, of necessity the nature of the therapy provided requires that the medicament make the compound of Formula I immediately available to the patient to whom it is being administered. There is a paucity of immediate release formulations reported at the present time based on solid dispersions or solutions of a class II API in a polymer matrix.